From the Guidelines
For a patient with macrocytosis without anemia, the recommended laboratory workup should include a complete blood count with peripheral smear, vitamin B12 and folate levels, liver function tests, thyroid function tests, reticulocyte count, and serum methylmalonic acid and homocysteine levels. This approach is based on the most recent and highest quality study available, which emphasizes the importance of identifying the underlying cause of macrocytosis to prevent progression to more severe hematologic abnormalities 1.
The initial workup should focus on identifying common causes of macrocytosis, such as:
- Vitamin deficiencies (B12 and folate)
- Liver disease
- Alcoholism
- Medication effects
The peripheral smear is particularly important as it can reveal characteristic morphological changes that suggest specific etiologies. Additional testing for hemolysis (LDH, haptoglobin), myelodysplastic syndrome (bone marrow examination), and medication review should be considered if the initial tests are inconclusive. Checking for alcohol use is essential as it's a common cause of macrocytosis even without anemia. The rationale for this approach is that macrocytosis often serves as an early indicator of underlying pathology before anemia develops, and identifying the cause can prevent progression to more severe hematologic abnormalities. Even without anemia, macrocytosis may indicate important metabolic or nutritional deficiencies that require correction, as highlighted in a recent study on the management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy 1.
Some key points to consider in the workup and evaluation of macrocytosis without anemia include:
- History and physical examination
- Blood chemistry and CBC with evidence of macrocytosis
- Evaluation for viral or bacterial causes of hemolysis
- Autoimmune serology and PNH screening
- Direct and indirect bilirubin, direct agglutinin test, and bone marrow analysis if no obvious cause is found. It is essential to prioritize the most recent and highest quality study available, which in this case is from 2021 1, to ensure that the recommended laboratory workup is based on the latest evidence and guidelines.
From the Research
Lab Workup for Macrocytosis without Anemia
The recommended lab workup for a patient with macrocytosis without anemia includes:
- History and physical examination to identify potential causes such as alcoholism, liver disease, and hypothyroidism 2
- Vitamin B12 level to rule out deficiency 2, 3, 4, 5
- Reticulocyte count to differentiate between drug or alcohol toxicity and hemolysis or hemorrhage 2, 3, 4
- Peripheral smear to identify megaloblastic anemia (macro-ovalocytes and hyper-segmented neutrophils) or non-megaloblastic macrocytosis 2, 3, 4, 5
- Thyroid and liver function tests to evaluate for hypothyroidism and liver disease 3, 4
- Bone marrow biopsy may be considered if cytopenias are present, although the yield may be lower in patients without anemia 6
Additional Tests
Additional tests that may be ordered include:
- Serum folate level to rule out folate deficiency 2, 3, 4, 5
- Schilling test to evaluate vitamin B12 absorption 3, 5
- Plasma uptake test to evaluate vitamin B12 absorption 5
- Bone marrow aspirate and biopsy with cytogenetic analysis to confirm a diagnosis of myelodysplasia or other bone marrow disorders 4
Follow-up
Patients with unexplained macrocytosis without anemia should be followed up closely, with blood cell counting every 6 months, as they may be at risk of developing a primary bone marrow disorder or worsening cytopenias 6